Biology subjects

van der Zande, H. J.

Publications and source records attributed to van der Zande, H. J..

3 recordsLinked to original sources

bioRxiv2025

Totum-448, a polyphenol-rich plant extract, decreases hepatic steatosis and inflammation in diet-induced MASLD mice

The increasing prevalence of obesity-driven metabolic dysfunction-associated steatotic liver disease (MASLD) urges the development of new therapeutic strategies. Totum-448 is a unique patented combination of polyphenol-rich plant extracts designed to reduce hepatic steatosis, a risk factor for steatohepatitis and type 2 diabetes. In this study, we investigated the effects of Totum-448 on metabolic homeostasis and steatohepatitis in diet-induced MASLD mice. For this purpose, male C57Bl6/J mice were fed a high-fat diet in combination with sucrose-containing drinking water for 12 weeks, followed by diet supplementation with or without Totum-448 for 4 weeks. Body weight/composition, caloric intake, plasma parameters and whole-body glucose tolerance were measured throughout the study and fecal microbiota composition was determined by 16S sequencing. Hepatic steatosis, transcriptomic/lipidomic profiles and immune cell composition were assessed by histological/biochemical assays, RNA sequencing, MS-based lipidomics, and spectral flow cytometry. We found that Totum-448 significantly lowered hyperinsulinemia and systemic glucose intolerance in MASLD mice without affecting body weight, fat mass, calorie intake, feces production or fecal microbiota composition. Furthermore, a decrease in liver MASLD activity score and macrovesicular steatosis, hepatic triglycerides and cholesterol contents, and plasma alanine aminotransferase levels were observed. Totum-448 also reduced the liver inflammatory and pro-fibrotic transcriptomic signatures and decreased both MASLD-induced loss in tissue-resident Kupffer cells and recruitment of monocyte-derived pro-inflammatory macrophages. Altogether, Totum-448 reduces hepatic steatosis and inflammation in insulin-resistant, steatotic, obese mice, a dual effect that likely contributes to improved whole-body metabolic homeostasis. Supplementation with Totum-448 may therefore constitute a promising novel nutritional approach for MASLD patients.

physiology↗

bioRxiv2022

Fasciola hepatica Fatty Acid Binding Protein 1 modulates T cell polarization by promoting dendritic cell thrombospondin-1 secretion without affecting metabolic homeostasis in obese mice

BackgroundThe parasitic trematode Fasciola hepatica evades host immune defenses through secretion of various immunomodulatory molecules. Fatty Acid Binding Proteins (fhFABPs) are among the main excreted/secreted proteins and have been shown to display anti-inflammatory properties. However, little is currently known regarding their impact on dendritic cells (DCs) and their subsequent capacity to prime specific CD4+ T cell subsets. Methodology/Principal FindingsThe immunomodulatory effects of both native F. hepatica extracts and recombinant fhFABPs were assessed on monocyte-derived human DCs (moDCs) and the underlying mechanism was next investigated using various approaches, including DC-allogenic T cell co-culture and DC phenotyping through transcriptomic, proteomic and FACS analyses. We mainly showed that fhFABP1 induced a tolerogenic-like phenotype in LPS-stimulated moDCs characterized by a dose-dependent increase in the cell-surface tolerogenic marker CD103 and IL-10 secretion, while DC co-stimulatory markers were not affected. A significant decrease in secretion of the pro-inflammatory cytokines IL-12p70 and IL-6 was also observed. In addition, these effects were associated with an increase in both Th2-on-Th1 ratio and IL-10 secretion by CD4+ T cells following DC-T cell co-culture. RNA sequencing and targeted proteomic analyses identified thrombospondin-1 (TSP-1) as a non-canonical factor highly expressed and secreted by fhFABP1-primed moDCs. The effect of fhFABP1 on T cell skewing was abolished when using a TSP-1 blocking antibody during DC-T cell co-culture. Immunomodulation by helminth molecules has been linked to improved metabolic homeostasis during obesity. Although fhFABP1 injection in high-fat diet-fed obese mice induced a potent Th2 immune response in adipose tissue, it did not improved insulin sensitivity or glucose homeostasis. Conclusions/SignificanceWe show that fhFABP1 modulates T cell polarization, notably by promoting DC TSP-1 secretion in vitro, without affecting metabolic homeostasis in a mouse model of type 2 diabetes.

immunology↗

bioRxiv2020

Soluble mannose receptor induces pro-inflammatory macrophage activation andobesity-associated metaflammation

Pro-inflammatory activation of macrophages in metabolic tissues is critically important in induction of obesity-induced metaflammation. Here, we demonstrate that the soluble mannose receptor (sMR) plays a direct, functional role in both macrophage activation and metaflammation. We show that sMR binds CD45 on macrophages and inhibits its phosphatase activity, leading to a Src/Akt/NF-{kappa}B-mediated cellular reprogramming towards an inflammatory phenotype both in vitro and in vivo. Remarkably, increased serum sMR levels were observed in obese mice and humans and directly correlated with body weight. Additionally, MR deficiency lowers pro-inflammatory macrophages in metabolic tissues and protects against hepatic steatosis and whole-body metabolic dysfunctions in high-fat diet-induced obese mice. Conversely, administration of sMR in lean mice increases serum pro-inflammatory cytokines, activates tissue macrophages and promotes insulin resistance. Altogether, our results reveal sMR as novel regulator of pro-inflammatory macrophage activation which could constitute a new therapeutic target for metaflammation and other hyperinflammatory diseases.

immunology↗